Use of levodopa, carbidopa and entacapone for treating Parkinson&#39;s disease

ABSTRACT

The present disclosure provides a method for the treatment of Parkinson&#39;s disease comprising simultaneously or sequentially administering to a patient in need of treatment of Parkinson&#39;s disease a dosage form comprising(i) levodopa in an amount ranging from 50 mg to 300 mg,(ii) carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.3:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to 1.54:1.0 by weight. Pharmaceutical dosage form used in said method are also disclosed.

This is a continuation of pending application Ser. No. 14/504,925, filedOct. 2, 2014, which is a continuation of application Ser. No.13/582,427, filed Sep. 2, 2012 (abandoned), which is a national stageapplication of International Application No. PCT/FI2011/000013, filed onMar. 3, 2011, which claims the benefit of priority of U.S. ProvisionalApplication Nos. 61/310,398, filed Mar. 4, 2010; 61/412,821, filed Nov.12, 2010; and 61/438,416, filed Feb. 1, 2011, all of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates to a method for the treatment ofParkinson's disease as well as to pharmaceutical dosage forms used insaid method.

BACKGROUND OF THE INVENTION

Levodopa ((−)-L-alpha-amino-beta-(3,4-dihydroxybenzene)propanoic acid)is a commonly used drug in the treatment of Parkinson's disease (PD). Itis commercially available as a combination with an aromatic amino aciddecarboxylase (AADC) inhibitor such as carbidopa((−)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene)propionicacid) monohydrate) or benserazide hydrochloride(N-DL-seryl)-N′-(2,3,4-trihydroxy-benzyl)hydrazine hydrochloride). Thecombination of levodopa with carbidopa is sold under, for instance, thetrademarks SINEMET®, DUODOPA® and PARCOPA® and the combination withbenserazide hydrochloride is sold under, for instance, the trademarkMADOPAR®.

Entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-diethyl-2propenamide) is a catechol-O-methyl transferase (COMT) inhibitor that isused in combination with levodopa and carbidopa or benserazide to treatParkinson's disease. It is commercially available as a stand-aloneformulation under, for instance, the trademarks COMTESS® and COMTAN® andas a fixed combination (levodopa:carbidopa:entacapone: 50 mg:12.5 mg:200mg, 75 mg:18.75 mg:200 mg, 100 mg:25 mg:200 mg, 125 mg:31.25 mg:200 mg,150 mg:37.5 mg:200 mg and 200 mg:50 mg:200 mg) under, for instance, thetrademark STALEVO®.

Typically, the proportion of levodopa to carbidopa (when calculated asanhydrate) or benserazide hydrochloride in commercial formulations is4:1 (or sometimes also 10:1 with carbidopa) by weight and the proportionof entacapone to carbidopa or benserazide hydrochloride, respectively,is at least 4:1 by weight. None of the above-cited products nor anypublication, of which applicants are aware, discloses the simultaneousor sequential administration of levodopa, carbidopa (or benserazidehydrochloride) and entacapone to a human in a repeated manner, whereinthe proportion of entacapone to carbidopa is less than 4:1 by weight.

Tolcapone (3,4-dihydroxy-4′-methyl-5-nitro-benzophenone) is another COMTinhibitor that is used as a 100 mg or 200 mg stand-alone formulationadministered three times daily as an adjunct to the levodopa/carbidopaor levodopa/benserazide treatment, the proportions of levodopa to theAADC inhibitor being the same as those used with entacapone. Tolcaponeis sold under trademark TASMAR® and its preparation has been disclosedin EP 0 237 929.

WO 2007/013830 discloses several COMT inhibitors including BIA 9-1067(5-[3-(2,5-dichloro-4,6-dimethyl-1-oxypyridin-3-yl-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol),which is undergoing clinical evaluation. WO 2000/37423 discloses BIA3-201 (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone, nebicapone).

WO 2007/010085 discloses new COMT inhibitor such as(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone,3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic aciddiethylamide,(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone,3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acidphenylamide,3-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-benzoicacid,4-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-benzoicacid, 3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid(4-methoxy-phenyl)amide,(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-yl)-methanone.(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl-methanone,which are believed to be much more potent than entacapone and tolcaponedue to their slower elimination via glucuronidation,

For the purposes of this disclosure, the COMT inhibitors disclosed in WO2007/010085 as well as BIA 9-1067 are considered to belong to a class of“highly potent COMT inhibitors.” The predicted standard dose (the doserecommended to be used together with the above mentioned conventionalproportion of levodopa to carbidopa) for a highly potent COMT inhibitorranges from 0.1 mg to 50.

For the purposes of this disclosure, tolcapone and other such COMTinhibitors, the standard dose of which ranges from more than 50 mg to200 mg, are considered to belong to a class of “moderately potent COMTinhibitors.”

SUMMARY OF THE INVENTION

U.S. Provisional Patent Application No. 61/310,398 filed Mar. 4, 2010,is hereby incorporated by reference.

The present disclosure provides a method for the treatment ofParkinson's disease (PD) comprising simultaneously or sequentiallyadministering to a patient in need of treatment of Parkinson's disease

(i) levodopa in an amount ranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 byweight, a moderately potent COMT inhibitor in an amount ranging from 25mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidoparanges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMTinhibitor in an amount ranging from 1 mg to 100 mg, wherein theproportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to1.54:1.0 by weight.

The present disclosure also provides a a dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.33:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in anamount ranging from 25 mg to 200 mg, wherein the proportion of said COMTinhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to3.08:1.0 by weight, or a highly potent COMT inhibitor in an amountranging from 1 mg to 100 mg, wherein the proportion of said COMTinhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to1.54:1.0 by weight.

Patients that may benefit the most from the invention are those whoseParkinson's disease symptoms or motor complications such as on/offfluctuations have not been adequately controlled with their existinglevodopa-AADC inhibitor therapy. Thus, a typical patient to be treatedis an adult patient with Parkinson's disease having symptoms ofend-of-dose wearing off.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean levodopa plasma concentrations (ng/ml) by studytreatments:

A: Entacapone 200 mg+levodopa 100 mg+carbidopa 25 mg

B: Entacapone 200 mg+levodopa 100 mg+carbidopa 50 mg

C: Entacapone 200 mg+levodopa 100 mg+carbidopa 100 mg

E: Levodopa 100 mg+carbidopa 25 mg

F: Levodopa 100 mg t carbidopa 50 mg

G: Levodopa 100 mg+carbidopa 100 mg.

FIG. 2 shows the mean carbidopa plasma concentrations (ng/ml) by studytreatments:

A: Entacapone 200 mg+levodopa 100 mg+carbidopa 25 mg

B: Entacapone 200 mg+levodopa 100 mg+carbidopa 50 mg

C: Entacapone 200 mg+levodopa 100 nig+carbidopa 100 mg

E: Levodopa 100 mg+carbidopa 25 mg

F: Levodopa 100 mg+carbidopa 50 mg

G: Levodopa 100 mg+carbidopa 100 mg.

FIG. 3 shows mean levodopa concentrations in human with increasedcarbidopa dose and with increasing COMT-inhibition either by increasingthe entacapone dose or by using the moderately potent COMT inhibitor,tolcapone.

DETAILED DESCRIPTION OF THE INVENTION

The most effective therapy for symptom control in Parkinson's Disease islevodopa therapy. However, with disease progression and long-termlevodopa treatment, PD patients frequently experience motorcomplications, including wearing-WO off symptoms such as “end-of-dosewearing off” symptoms, “early morning dystonia” and “on/offfluctuations,” and dyskinesia.

During end-of-dose wearing off, the effect of a dose of a PD drugdecreases (wears off), the drug concentration decreases in plasma andsubsequently in the brain, and the severity of PD symptoms, e.g.,bradykinesia, rigidity, and resting tremor, are increased before thenext dose is taken. Partly related to the motor symptoms and partly tothe autonomic dysfunction, a PD patient with “end-of-dose wearing off”or “on/off fluctuations” may experience poor gastrointestinal tractmobility and swallowing difficulties.

In addition to the symptoms relating to motor function, the wearing-offsymptoms may also include non-motor symptoms such as anxiety and pain.The reasons for the fluctuation episodes are not completely understoodbut may be, in part, related to oscillating plasma levels of levodopa inturn leading to intermittent or pulsatile stimulation of striatialdopamine receptors in the brain. End-of-dose wearing off symptoms oron/off fluctuations comprise alterations between periods of relativelygood mobility (“on” periods) and periods of relatively impaired motorfunction (“off” periods) often associated with simultaneous non-motorsymptoms. Dyskinesia are involuntary movements in the body of a PDpatient often associated with high maximum or peak concentrations of aPD drug, such as levodopa. Thus, there is a continuing need to improvethe present levodopa therapies by striving towards more steady plasmalevels of levodopa and subsequently more continuous dopaminergicstimulation.

The inventors have surprisingly found that, in combination with a COMTinhibitor, AADC inhibition is not saturated by the currently usedcarbidopa dose, as with levodopa-carbidopa combination alone, but may befurther enhanced by increased carbidopa doses, which may lead toimproved levodopa pharmacokinetics and metabolism and subsequently maylead to improved control of PD symptoms and motor complications.

Unlike in traditional levodopa therapy, there may be no need to maintaina standard levodopa/carbidopa ratio (such as 4:1) across all dosagestrengths, when using the treatment according to the invention.Furthermore, in combination with a COMT inhibitor, increased carbidopadoses may potentiate the pharmacodynamic effect on the AADC inhibitionand subsequently may increase levodopa AUC throughout the dosing perioddespite the decreasing carbidopa plasma concentrations towards the endof said period. This is because by the increased carbidopa dose in thepresence of a COMT inhibitor Cmin and AUC of levodopa are significantlyincreased. This means that, when a COMT inhibitor is given inconjunction with levodopa and an aromatic amino acid decarboxylaseinhibitor, such as carbidopa, plasma levels of levodopa are higher andmore sustained with the increased carbidopa dose than afteradministration of levodopa and an aromatic amino acid decarboxylaseinhibitor alone.

It is believed that, at a given daily frequency of levodopaadministration, those more sustained plasma levels of levodopa resultingfrom an increased carbidopa dose yield more constant dopaminergicstimulation in the brain, leading to improved control of the signs andsymptoms of Parkinson's Disease, especially in end-of-dose wearing offand on/off fluctuations and in. As maximum concentrations of levodopaare not clinically significantly increased, the improved control of thesigns and symptoms of Parkinson's Disease are not accompanied byincrease of dopaminergic adverse effects or motor complications, such asdyskinesia, which would require reducing of the levodopa dose.

Furthermore, as the effect on levodopa is not sensitive to decreasedplasma concentration of carbidopa towards the end of said period, noaccumulation of carbidopa concentrations in plasma is seen. In fact, inthe study, the concentrations were decreasing towards the end of thedosing period, which will reduce the probability of carbidopa passingthe blood brain barrier and inhibiting AADC in the brain followed bysubsequent increase of CNS side effects.

In combination with increased carbidopa dose, the COMT-inhibitor dosecan also be reduced without significantly reducing AUC of levodopa.Reducing the amount of COMT-inhibitor would allow a smaller tablet sizewhich would in turn benefit especially patients with swallowingdifficulties. This would also be advantageous to reduce the risk of COMTinhibitor related gastrointestinal irritation and urine discoloration.

In combination with increased carbidopa dose, the COMT-inhibitor dose orpotency can also be increased to an extent that will not significantlyincrease Cmax but win increase AUC of levodopa. Increasing theCOMT-inhibitor potency would allow better control of PD symptoms. Thiswould be advantageous to PD patients with wearing-off symptoms such asend-of-dose wearing off, early morning dystonia, and on/offfluctuations.

Thus, the present disclosure provides a method for the treatment ofParkinson's disease comprising simultaneously or sequentiallyadministering to a patient in need of treatment of Parkinson's disease

(i) levodopa in an amount ranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 byweight, a moderately potent COMT inhibitor in an amount ranging from 25mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidoparanges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMTinhibitor in an amount ranging from 1 mg to 100 mg, wherein theproportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to1.54:1.0 by weight.

In one embodiment, the patient to be treated is an adult patient withParkinson's disease experiencing symptoms of end-of-dose wearing off.

The present disclosure also provides a dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.33:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in anamount ranging from 25 mg to 200 mg, wherein the proportion of said COMTinhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to3.08:1.0 by weight, or a highly potent COMT inhibitor in an amountranging from 1 mg to 100 mg, wherein the proportion of said COMTinhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to1.54:1.0 by weight.

The present disclosure also provides levodopa, an aromatic amino aciddecarboxylase inhibitor, and entacapone for use in a method of treatmentof Parkinson's disease by simultaneous or sequential administration to apatient of

(i) levodopa in an amount ranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 byweight, a moderately potent COMT inhibitor in an amount ranging from 25mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidoparanges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMTinhibitor in an amount ranging from 1 mg to 100 mg, wherein theproportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to1.54:1.0 by weight, optionally wherein carbidopa is replaced by atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor.

The present disclosure also provides use of levodopa, an aromatic aminoacid decarboxylase inhibitor, and entacapone in the manufacture of amedicament for the treatment of Parkinson's disease by simultaneous orsequential administration to a patient of (i) levodopa in an amountranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 byweight, a moderately potent COMT inhibitor in an amount ranging from 25mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidoparanges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMTinhibitor in an amount ranging from 1 mg to 100 mg, wherein theproportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to1.54:1.0 by weight, optionally wherein carbidopa is replaced by atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor.

The present disclosure also provides a dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 300 mg,

(ii) carbidopa in an amount ranging from 25 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.33:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in anamount ranging from 25 mg to 200 mg, wherein the proportion of said COMTinhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to3.08:1.0 by weight, or a highly potent COMT inhibitor in an amountranging from 1 mg to 100 mg, wherein the proportion of said COMTinhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to1.54:1.0 by weight, for simultaneous or sequential use in the treatmentof Parkinson's disease.

The present disclosure also provides a kit for simultaneous orsequential administration of levodopa, carbidopa or a therapeuticallyequivalent amount of another aromatic amino acid decarboxylaseinhibitor, and entacapone, a moderately potent COMT inhibitor, or ahighly potent COMT inhibitor, comprising:

(i) levodopa in an amount ranging from 50 mg to 300 mg;

-   -   (ii) carbidopa in an amount ranging from 25 mg to 150 mg or a        therapeutically equivalent amount of another aromatic amino acid        decarboxylase inhibitor; and        (iii) entacapone in an amount ranging from 50 mg to 300 mg,        wherein the proportion of entacapone to carbidopa in said        administration ranges from 0.33:1.0 to 3.2:1.0 by weight, a        moderately potent COMT inhibitor in an amount ranging from 25 mg        to 200 mg, wherein the proportion of said COMT inhibitor to        carbidopa in said administration ranges from 0.16:1.0 to        3.08:1.0 by weight, or a highly potent COMT inhibitor in an        amount ranging from 1 mg to 100 mg, wherein the proportion of        said COMT inhibitor to carbidopa in said administration ranges        from 0.006:1.0 to 1.54:1.0 by weight, wherein the kit may        further comprise instructions for the simultaneous or sequential        administration of the levodopa, carbidopa or a therapeutically        equivalent amount of another aromatic amino acid decarboxylase        inhibitor, and entacapone, a moderately potent COMT inhibitor,        or a highly potent COMT inhibitor in the treatment of        Parkinson's disease.

In one embodiment, levodopa is present in an amount ranging from 50 mgto 200 mg, carbidopa is present in an amount ranging from 65 mg to 125mg, and entacapone is present in an amount ranging from 100 mg to 200mg, wherein the proportion of entacapone to carbidopa ranges from0.8:1.0 to 3.08:1.0 by weight.

In one embodiment, levodopa is present in an amount ranging from 75 mgto 175 mg, carbidopa is present in an amount ranging from 65 mg to 105mg, and entacapone is present in an amount ranging from 100 mg to 200mg, wherein the proportion of entacapone to carbidopa ranges from0.95:1.0 to 3.08:1.0 by weight.

In one embodiment of the invention, levodopa is present in an amountranging from 50 mg to 300 mg, for instance from 50 mg to 200 mg, such asfrom 75 mg to 125 mg, for example 50 mg, 75 mg, 100 mg, 125 mg, 150 mg,or 200 mg, for example 75 mg, 100 mg, 125 mg, 150 mg.

In one embodiment, carbidopa is present in an amount ranging from 65 mgto 150 mg, for instance from 65 mg to 125 mg, such as from 65 mg to 105mg, for example 65 mg, 80 mg, 85 mg, 105 mg, or 125 mg.

In one embodiment, entacapone is present in an amount ranging from 50 mgto 300 mg, for instance from 50 mg to 200 mg, such as from 100 mg to 200mg, for example 100 mg, 150 mg or 200 mg.

In one embodiment, the moderately potent COMT inhibitor, such astolcapone, is present in an amount ranging from 25 mg to 200 mg, forinstance from 50 mg to 200 mg, such as from 50 mg to 100 mg, for example50 mg, 100 mg, or 200 mg.

In one embodiment, the highly potent COMT inhibitor, such as BIA 9-1067,is present in an amount ranging from 1 mg to 100 mg, for instance from 1mg to 50 mg, such as from 1 mg to 25 mg, for example 1 mg, 2.5 mg, 5 mg,10 mg, or 25 mg.

In one embodiment, carbidopa is replaced by a therapeutically equivalentamount of another aromatic amino acid decarboxylase inhibitor, such asfor instance with benserazide.

In one embodiment, the treatment and/or the dosage form is oral.

In one embodiment the treatment comprises administering orally a solidcombination formulation.

In a further embodiment, the oral dosage form is an oral solidcombination formulation

In one embodiment, the proportion of entacapone to carbidopa ranges from0.33:1.0 to 3.08:1.0 by weight, for instance from 0.8:1.0 to 2.35:1.0 byweight.

In one embodiment, the proportion of entacapone to carbidopa is0.66:1.0, 0.80:1.0, 0.95:1.0, 1.18:1.0, 1.33:1.0, 1.54:1.0, 1.6:1.0,1.9:1.0, 2.35:1.0, 2.5:1.0, or 3.08:1.0 by weight.

In one embodiment, the proportions of entacapone and carbidopa are 100mg:125 mg, 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200mg:125 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, 200 mg:65 mg.

In one embodiment, the proportion of levodopa to carbidopa ranges from0.4:1.0 to 3.1:1.0 by weight, for instance from 0.48:1.0 to 1.91:1.0 byweight.

In one embodiment, the proportions of levodopa and carbidopa are 50mg:45 mg, 50 mg:65 mg, 50 mg:80 mg, 50 mg:85 mg, 50 mg:105 mg, 50 mg:125mg, 75 mg:45 mg, 75 mg:65 mg, 75 mg:80 mg, 75 mg:85 mg, 75 mg:105 mg, 75mg:125 mg, 100 mg:45 mg, 100 mg:65 mg, 100 mg:80 mg, 100 mg:85 mg, 100mg:105 mg, 100 mg:125 mg, 125 mg:45 mg, 125 mg:65 mg, 125 mg:80 mg, 125mg:85 mg, 125 mg:105 mg, 125 mg:125 mg, 150 mg:45 mg, 150 mg:65 mg, 150mg:80 mg, 150 mg:85 mg, 150 mg:105 mg, 150 mg:125 mg, 200 mg:65 mg, 200mg:80 mg, 200 mg:85 mg, 200 mg:105 mg, or 200 mg:125 mg.

In one embodiment, the proportions of levodopa, carbidopa and entacaponeare 50 mg:65 mg:200 mg, 50 mg:80 mg:200 mg, 50 mg:85 mg:200 mg, 50mg:105 mg:200 mg, 50 mg:125 mg:200 mg, 75 mg:65 mg:200 mg, 75 mg:80mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 75 mg:125 mg:200 mg,100 mg:85 mg:200 mg, 100 mg:80 mg:200 mg, 100 mg:85 mg:200 mg, 100mg:105 mg:200 mg, 100 mg:125 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:80mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 125 mg:125 mg:200mg, 150 mg:65 mg:200 mg, 150 mg:80 mg:200 mg, 150 mg:85 mg:200 mg, 150mg:105 mg:200 mg, 150 mg:125 mg:200 mg, mg, 200 mg:65 mg:200 mg, 200mg:80 mg:200 mg, 200 mg:85 mg:200 mg, 200 mg:105 mg:200 mg, or 200mg:125 mg:200 mg.

In one embodiment, the proportions of levodopa, carbidopa and entacaponeare 50 mg:65 mg:200 mg, 50 mg:80 mg:200 mg, 50 mg:85 mg:200 mg, 50mg:105 mg:200 mg, 75 mg:65 mg:200 mg, 75 mg:80 mg:200 mg, 75 mg:85mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:80 mg:200mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125mg:80 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65mg:200 mg, 150 mg:80 mg:200 mg, 150 mg:85 mg:200 mg, 150 mg:105 mg:200mg, 200 mg:65 mg:200 mg, 200 mg:80 mg:200 mg, 200 mg:85 mg:200 mg, or200 mg:105 mg:200 mg.

In one embodiment, the proportions of levodopa, carbidopa and entacaponeare 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg.

In one embodiment of the invention, the daily dose of levodopa rangesfrom 150 mg to 1500 mg, for instance from 300 mg to 1250 mg, such asfrom 300 mg to 900 mg, wherein the total number of daily doses rangesfrom 3 to 10, for instance from 3 to 7, such as from 4 to 6, such as 4or 5 or 6.

In one embodiment of the invention, the daily dose of carbidopa rangesfrom 135 mg to 1250 mg, for instance from 195 mg to 1050 mg, such asform 255 mg to 850 mg, wherein the total number of daily doses rangesfrom 3 to 10, for instance from 3 to 7, such as from 4 to 6, such as 4or 5 or 6.

In one embodiment of the invention the highly potent COMT inhibitor isBIA 9-1067(5-[3-(2,5-dichloro-4,6-dimethyl-1-oxypyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol)lnone embodiment the daily dose of BIA 9-1067 is 25 mg or 50 mg givenonce-a-day. BIA 9-1067 is a poorly soluble drug. WO 2009/108077discloses a solid dosage form for the release of a poorly soluble activepharmaceutical ingredient such as BIA 9-1067.

In one embodiment the proportion of BIA 9-1067 to carbidopa ranges from0.01:1.0 to 0.16:1.0 by weight, for instance from 0.02:1.0 to 0.1:1.0 byweight.

In one embodiment the proportions of BIA 9-1067 and carbidopa are 2.5mg:65 mg, 2.5 mg:85 mg, 2.5 mg:105 mg, 5.0 mg:65 mg, 5.0 mg:85 mg, 5.0mg:105 mg, 10.0 mg:65 mg, 10.0 mg:85 mg or 10.0 mg:105 mg.

In one embodiment the proportions of levodopa, carbidopa and BIA 9-1067are 75 mg:65 mg:2.5 mg, 75 mg:85 mg:2.5 mg, 75 mg:105:2.5 mg, 100 mg:65mg:2.5 mg, 100 mg:85 mg:2.5 mg, 100 mg:105 mg:2.5 mg, 125 mg:65 mg:2.5mg, 125 mg:85 mg:2.5 mg, 125 mg:105 mg:2.5 mg, 150 mg:65 mg:2.5 mg, 150mg:85 mg:2.5 mg, 150 mg:105 mg:2.5 mg, 75 mg:65 mg:5.0 mg, 75 mg:85mg:5.0 mg, 75 mg:105:5.0 mg, 100 mg:65 mg:5.0 mg, 100 mg:85 mg: 5.0 mg,100 mg:105 mg:5.0 mg, 125 mg:65 mg:5.0 mg, 125 mg:85 mg:5.0 mg, 125mg:105 mg:5.0 mg, 150 mg:65 mg:5.0 mg, 150 mg:85 mg:5.0 mg, 150 mg:105mg:5.0 mg, 75 mg:65 mg:10.0 mg, 75 mg:85 mg:10.0 mg, 75 mg:105:10.0 mg,100 mg:65 mg:10.0 mg, 100 mg:85 mg: 10.0 mg, 100 mg:105 mg:10.0 mg, 125mg:65 mg:10.0 mg, 125 mg:85 mg:10.0 mg, 125 mg:105 mg:10.0 mg, 150 mg:65mg:10.0 mg, 150 mg:85 mg:10.0 mg, 150 mg:105 mg:10.0 mg.

In one embodiment of the invention, the daily dose of entacapone rangesfrom 150 mg to 2000 mg, for instance from 300 mg to 2000 mg, such asfrom 300 mg to 1600 mg, wherein the total number of daily doses rangesfrom 3 to 10, for instance from 3 to 8, such as from 4 to 6, such as 4or 5 or 6. In one embodiment of the invention, the daily dose oftolcapone or another moderately potent COMT inhibitor ranges from 75 mgto 1200 mg, for instance from 150 mg to 800 mg, such as from 300 mg to600 mg, wherein the total number of daily doses ranges from 3 to 10, forinstance from 3 to 7, such as from 3 to 5, such as 3 or 4 or 5. In oneembodiment of the invention, the daily dose of a highly potent COMTinhibitor ranges from 1 mg to 500 mg, for instance from 5 mg to 100 mg,such as from 10 mg to 100 mg, wherein the total number of daily dosesranges from 1 to 10, for instance from 1 to 7, such as from 1 to 3, suchas 1 or 2 or 3.

It is to be understood that whenever a given amount of levodopa,carbidopa, benserazide, or other AADC inhibitor or entacapone or otherCOMT inhibitor is mentioned herein in the context of this disclosure itis meant to comprise also an equivalent amount of a pharmaceuticallyacceptable salt, prodrug (including ester) or hydrate.

It is also to be understood that the amounts and ranges mentioned inthis disclosure apply to all embodiments disclosed herein whethermethods (i.e. methods for the treatment or methods for the manufacture)or dosage forms.

Definitions

The term “treatment of Parkinson's Disease” refers to relieving and/ordelaying of the worsening of one of more of the symptoms and/or motorcomplications related to idiopathic Parkinson's Disease, e.g.bradykinesia, rigidity, and resting tremor.

The term “adult patient” means a patient 18 years of age or older.

The term “symptoms of end-of-dose wearing-off” refers to the shorteningof the duration of the motor response after a PD drug intake andincreasing the severity of e.g. bradykinesia, rigidity, and restingtremor. The term comprises the so-called predictable end-of-dose motorfluctuations characterised by end-of-dose failure of the symptomcontrol. End-of-dose wearing-off symptoms may also include fluctuatingnon-motor symptoms, such as anxiety and pain. Motor complications mayalso include rapid and unpredictable swings from mobility to immobility(“on-off” phenomenon).

The term “simultaneous” or “simultaneously” refers to administration ofthe disclosed drug substances at the same time in separate formulationsor as a combination formulation, i.e. in a single dosage form.

The term “sequential” or “sequentially” refers to administration of thedisclosed drug substances one after the other. i.e., not at the sametime, in two or more separate dosage forms, for example entacapone maybe administered as a separate dosage form and levodopa and carbidopa maybe administered in a combination formulation, or carbidopa may beadministered, followed by levodopa, then by entacapone. If the discloseddrug substances are administered sequentially, then typicallyadministration of the last drug substance is begun an hour or less,generally 30 minutes or less, after administration of the first drugsubstance is begun.

The term “oral solid dosage form” refers to a single or multi-unit solidoral dosage form. A single oral dosage form may be a combinationformulation, such as a tablet, which comprises two or more of the drugsubstances. In one embodiment the single oral dosage form is acombination formulation, such as a tablet, which comprises all of thedrug substances. A multi-unit solid oral dosage form may be a dosageform comprising a plurality of oral solid units in the form of smallparticles (for instance a capsule or sachet filled with minitablets,granules or pellets) which, when taken simultaneously or sequentially,provide a unit dose. The terms “multiple-unit” or “multi-particulate”oral dosage form may also be used to refer to such a multi-unit solidoral dosage form. The particles may be also be used as such in aso-called sprinkle form that can be sprinkled directly onto food orliquids for easy ingestion. Multiple-unit dosage forms have beenaccepted to provide advantages over single unit dosage forms. Thepharmacokinetics of the drug release from a multiple unit dosage form ismore uniform than from the single unit dosage form, because thepharmacokinetics of the drug release from a multiple unit dosage form isthe average value of the kinetics of the drug release from individualsubunits. The units of a multiple unit dosage form may scatter freely inthe gastrointestinal tract and act like liquids, leaving the stomachwithin a short period of time, which results in improvedbiopharmaceutical characteristics, such as improved bioavailability,reduced food effect on plasma profiles and ultimately reducedvariability of plasma profiles and a lower possibility of localirritation in gastrointestinal tract. In addition, a multi-unit solidoral dosage form may be individual tablets that contain the drugsubstances. For example, a multi-unit solid oral dosage form can includeentacapone in one tablet and a separate tablet containing levodopa andcarbidopa.

The terms “repeated dose” and “in a repeated manner” refers to multipleadministration of a drug during a day, usually from at least 3 up to 10times a day depending on the severity of the disease of a patient withParkinson's Disease and on the subsequent need of levodopa. Forinstance, levodopa is usually administered in a repeated manner andsimultaneously or sequentially with an AADC inhibitor. However, a highlypotent COMT inhibitor may be administered in combination with repeateddose levodopa and AADC inhibitor only once a day or even less frequentlyand a moderately potent COMT inhibitor may be administered one to threetimes per day.

The “standard dose” may be used to determine whether a COMT inhibitormay be considered to be a highly potent inhibitor or a moderately potentinhibitor. As potency increases, less inhibitor is required to reach 80%inhibition of soluble COMT in human erythrocytes (Shultz, E. andNissinen, E., Biomedical Chromatography, Vol. 3, No. 2, 1989, 64-87 andNohta. H. et al, Journal of Chromatography, 308 (1984) 93-100). Forexample, a moderately potent COMT inhibitor will require more than 200mg in a single dose to reach 80% inhibition, typically from more than200 mg to 800 mg in a single dose. A highly potent inhibitor will need200 mg or less in a single dose to reach 80% inhibition. A more potentinhibitor will also provide effective inhibition for a longer period oftime. Thus, a moderately potent inhibitor when administered in a 200 mgdose will maintain 40% or more effective inhibition of soluble COMT inhuman erythrocytes for from 2 hours to less than 8 hours, typically from3 to 6 hours. A highly potent inhibitor when administered in a dose of100 mg will maintain 40% or more effective inhibition of soluble COMT inhuman erythrocytes for 8 hours or more. Suitable conditions formeasuring effective inhibition of soluble COMT in human erythrocytes aredescribed in Keränen, T. et al, Eur. J. Clin. Pharmcol (1994) 46:151-157and Dingemanse, J. et al, Clinical Pharmacology & Therapeutics, May1995, 508-517).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Representativeexamples of pharmaceutically acceptable salts include, but are notlimited to, acid addition salts with inorganic or organic acids, forinstance, chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, methane sulfonates, formates, tartrates, maleates, citrates,benzoates, salicylates, ascorbates, acetates, and oxalates. Thepharmaceutically acceptable form can be in the form of an anhydrate or ahydrate.

The term “prodrug” refers to a derivative of a drug substance whichreleases said active parent drug substance in vivo when such prodrug isadministered to a patient. There are several publications disclosingdifferent prodrugs of levodopa, for instance, levodopa methyl ester hasbeen under development by Chiesi under trademark LEVOMET®, an ethylesterhas been disclosed in U.S. Pat. No. 5,607,969 and more complex estershave been disclosed in EP 0 309 827 B, WO 20051121069 and WO2007/067495. Also, various carbidopa prodrugs have been disclosed e.g.in GB 940,596 and WO 2004/052841.

The term “ester” refers to an ester of a compound that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such esters may beprepared by known methods using pharmaceutically acceptable acids thatare conventional in the field of pharmaceuticals. Non-limiting examplesof these esters include esters of aliphatic or aromatic alcohols.Representative examples of pharmaceutically acceptable esters include,but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, and benzyl esters. There are severalpublications disclosing different esters of levodopa, for instance,several levodopa esters have been disclosed in EP 309 827, an ethylester has been disclosed in U.S. Pat. No. 5,607,969 and the methyl esterhas been under development by Chiesi under trademark LEVOMET®. Alsovarious carbidopa esters have been disclosed e.g. in GB 940,596. Thepharmaceutically acceptable form can be in the form of an anhydrate orhydrate.

The term “a therapeutically equivalent amount” as used herein refers toan amount of an aromatic amino acid decarboxylase inhibitor other thancarbidopa that is capable of causing a similar therapeutic response asthe dose of carbidopa, when used according to the present disclosure.For example, 50 mg of benserazide hydrochloride is considered to becapable of causing a similar therapeutic response as 50 mg of carbidopa,when used according to the present disclosure.

The terms “substantially separated” and “substantial separation” referto that a considerable or ample amount of said drug substance is keptapart from the other drug substance(s), for example, that a considerableamount of carbidopa is kept apart from entacapone. There may be severalways to accomplish said separation, for example, by granulating all orat least one of the drug substances separately. No specific separationlayer is needed to cause said substantial separation. It is also to benoted that even though all drug substances would be granulatedseparately, there will always be small amounts of said drug substance asa powder. In one embodiment, before granulating and incorporating a drugsubstance in a single dosage unit with other drug substances, they mayundergo pre-processing in a manner indicated below.

The term “substantial portion” refers to that at least 80% of said drugsubstance is handled using the technology in question. For instance,granulating a substantial portion of carbidopa means that from 80% to100% is granulated. If 90% is granulated, then 10% is added as such. Theterm “granule” refers to a pharmaceutical formulation whereby theingredients have been mixed together in order to intimately and evenlydisperse the drug substance(s) within some or all of the otheringredients and to increase the particle size. Well known techniques areknown in the pharmaceutical industry and can be selected from wet, meltgranulation or dry granulation.

The terms “granulating” and “granulation” refer to methods, wherein oneor more drug substances are brought into contact with at least onepharmaceutically acceptable excipient and granulated. The granulationmethod may be any granulation method known in the art such as drygranulation, melt granulation or wet granulation or the like. All unitoperations typically needed to perform granulation, such as sieving anddrying are meant to be included in said granulation step in the contextof this disclosure. Furthermore, it is possible to coat the granulesmade according to the invention, for instance, when they are intended tobe administered to the patient as such. Suitable granulation methodshave been described, for instance in the book: The Theory and Practiceof Industrial Pharmacy 3^(rd) edition, Lachman L, Lieberman H A andKanig J L, Lea & Febiger, Philadelphia, 1986 and the Handbook ofPharmaceutical Excipients 5^(th) edition, edited by Rowe R C, Sheskey PJ and Owen S C, Pharmaceutical Press, 2006. The details of thepharmaceutically acceptable excipients used therein have been described,for instance in Pharmaceutics, The Science of Dosage Form Design, 2^(nd)edition. Aulton M E, Churchill Livingstone, 2002. Suitable meltgranulation technologies have been described, for instance, in Handbookof Pharmaceutical Granulation Technology, Ed. by Dilip M. Parikh, MarcelDekker, Inc. New York, 2^(nd) print, 1997. The drug substances to beused in the granulation method may be pre-processed before thegranulation. Pre-processing may also generally be applied to drugsubstances before formulating into a dosage form without granulation.For example, a drug substance in the form of a powder may bepre-processed before formulation into a dosage form.

The terms “pre-processed” and “pre-processing” refer to pre-treatment ofeach of the drug substances, either individually or together withanother drug substance, before further processing, such as beforegranulation or before formulating a powder into a dosage form. Suitablepre-processing methods can be, for example, sieving, de-dusting, gastreatment, conditioning, milling and optionally mixing, de-aggregation,de-agglomeration or treatment with pharmaceutically acceptableexcipients, for example, with glidants such as colloidal silicondioxide.

The term “mixing” and “preparing a mixture” refer to the meaning used inthe art of manufacturing pharmaceutical dosage forms. Suitable mixingtechnologies have been described, for example in the above mentionedhandbooks.

The term “bilayered tablet” refers to a tablet, wherein there are twolayers horizontally on the top of each other or there is an inner corecomprising either one or two of the drug substances and an outer layercomprising at least one drug substance. For example, there may be anouter layer comprising carbidopa and levodopa or carbidopa alone and aninner core comprising entacapone and levodopa or entacapone alone. It isalso possible to divide one or more drug substances between two layers,for instance, carbidopa may be divided between the outer layer and theinner core. This type of tablets and the preparation thereof have beendescribed, for instance, in WO 2008/053297. Other suitable technologieshave been described, for instance in the book: The Theory and Practiceof Industrial Pharmacy 3^(rd) edition. Lachman L, Lieberman H A andKanig J L, Lea & Febiger, Philadelphia, 1986. It is to be noted thatthere may be always one or more inert layers (e.g. layers preparedwithout separately adding a drug substance) in such a bilayered tablet.Likewise, it is possible that there is an inert inner core, forinstance, a non-pareil inside the tablet.

The terms “trilayered tablet” and “multilayered” tablets refer totablets, wherein there are three or more layers horizontally on the topof each other or there is an inner core or layer comprising one of thedrug substances a second layer comprising another drug substance and athird layer comprising the third drug substance. For example, there maybe an outer layer comprising carbidopa and the next layer comprisinglevodopa and an inner core or layer comprising entacapone. It is alsopossible to divide one or more drug substance into several layers, forinstance, carbidopa may be divided between the outer layer and thesecond layer. Other suitable technologies have been described, forinstance in the book: Pharmaceutical Dosage Forms and Drug DeliverySystems, 7^(th) edition, Ansell H C, Allen L V and Popovich N G,Lippincott Williams & Wilkins, 1999. It is to be noted that there may bealways one or more inert layers (e.g. layers prepared without separatelyadding a drug substance) in such a trilayered or multilayered tablet.Likewise, it is possible that there is an inert inner core, forinstance, a non-pareil inside the tablet.

The term “minitablet” refers to a compressed pharmaceutical formulationthat has dimensions of length and breadth (or, depending on its shape, adiameter) each equal to or less than 5 mm.

The term “pellet” refers to a substantially spherical solid particlewhose diameter size may range from about 100 microns to about 3 mm thathas been made by layering onto a particle (for instance, on anon-pareil) or extrusion optionally followed by spheronisation or othersimilar known techniques. Generally pellets are more spherical inappearance than mini-tablets.

The term “immediate release” refers to a pharmaceutical dosage formwhich releases levodopa immediately upon administration and will resultin 80-100%, preferably 90-100% dissolution of the dose amount within onehour. Dissolution method: USP apparatus I: 50 rpm; medium: 0.1 Nhydrochloric acid, 750 ml.

The pharmaceutical dosage forms of the present invention can be presentin the form of monolayered or multilayered (for instance, bilayered ortrilayered tablets), minitablets, capsules, granules, pellets, orminitablets, granules, pellets or a combination of the same in a capsuleor the like.

There are several different ways to prepare the dosage form(s) accordingto the invention. In discussing the preparation of the dosage forms wewill, for simplicity, refer to the COMT inhibitor as entacapone. Howeverit should be understood that the methods described here for entacaponeare equally suitable for use with another COMT inhibitor in which theamount of the COMT inhibitor is adjusted as appropriate and as would beevident to the skilled person on the basis of the standard dose for theCOMT inhibitor. Similarly, for simplicity the aromatic amino aciddecarboxylase inhibitor is referred to as carbidopa, but it should beunderstood that the methods described are equally suitable for use withanother AADC inhibitor in which the amount of AADC inhibitor is adjustedas appropriate.

One way to prepare a dosage form according to the invention is to firstformulate carbidopa substantially separately from entacapone andlevodopa before formulating into the dosage form, for example, in themanner disclosed in U.S. Pat. No. 6,500,867 describing fixed oralcombinations of entacapone, levodopa and carbidopa, wherein carbidopa issubstantially separated from entacapone and levodopa. Another way is tofirst formulate entacapone substantially separately from levodopa andcarbidopa before formulating into the dosage form. One particular suchway is to use separate entacapone-containing granules or granulemixtures, for example using the technologies disclosed in WO20061131591, and combine said granules or granule mixtures with levodopaand AADC inhibitor either in a fixed combination formulation or as twoseparate dosage forms. A further way of preparing dosage forms accordingto the invention is to first formulate part of the levodopa content withentacapone and a further part of the levodopa content with carbidopa,before formulating into the dosage form optionally together with afurther part of the levodopa content added as such. A yet further way isto prepare a mixture of levodopa, carbidopa and entacapone, of which anypart may optionally be pre-processed, before formulating into the dosageform.

Thus, in one embodiment of the invention entacapone and carbidopa aresubstantially separated from each other. There are several differenttechniques to accomplish said separation. It can be made, for instance,by granulating levodopa and entacapone together or separately and addingcarbidopa as such (i.e. non-granulated carbidopa, for example, in powderform) and/or as granules; or by granulating levodopa and carbidopa andadding entacapone as such (i.e. non-granulated entacapone, for example,in powder form) or in the form of granules. Any known granulationmethod, for example, wet granulation, melt granulation and drygranulation can be used, but preferably the granulation method is wetgranulation. Suitable granulation methods are known in the art andsuitable excipients are listed in, for instance in WO 20061131591.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating substantial portion of entacapone and substantialportion of levodopa either together or separately

(b) optionally granulating all or any portion of carbidopa

(c) combining the product obtained in step (a) with the product of step(b) or carbidopa as such or a mixture thereof; and

(d) formulating the product obtained in step (c) as well as the rest ofentacapone and/or levodopa, if any, into tablets or minitablets orfilling the same directly into capsules, sachets or a dispenser. Thismethod is preferred, when flexibility in the release properties of thedrug substances is required.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating entacapone and levodopa either together or separately

(b) granulating carbidopa

(c) combining the product obtained in step (a) with the product of step(b); and

(d) formulating the product obtained in step (c) into tablets orminitablets.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating entacapone and levodopa either together or separately

(b) granulating from 5 to 80% of carbidopa

(c) combining the product obtained in step (a) with the product of step(b) and the rest of carbidopa as such; and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling the same directly into capsules, sachets or adispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating entacapone and levodopa either together or separately

(b) granulating from 5 to 40% of carbidopa

(c) combining the product obtained in step (a) with the product of step(b) and the rest carbidopa as such; and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling the same directly into capsules, sachets or adispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating entacapone and levodopa either together or separately

(b) granulating from 15 to 20% of carbidopa

(c) combining the product obtained in step (a) with the product of step(b) and the rest carbidopa as such; and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling the same directly into capsules, sachets or adispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating entacapone and levodopa either together or separately

(b) combining the product obtained in step (a) with carbidopa as such;and

(c) formulating the product obtained in step (c) into tablets. Thismethod provides a simple manufacturing process and a good stability forthe product.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) formulating a substantial portion of entacapone and a substantialportion of levodopa either together or independently into granules,minitablets or pellets

(b) formulating a substantial portion of carbidopa into granules,minitablets or pellets; and

(c) combining the product obtained in step (a) with the product of step(b) and the rest of the drug substances if any, and filling it intocapsules, sachets or a dispenser.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) formulating a substantial portion of entacapone and a substantialportion of levodopa either together or independently into granules,minitablets or pellets

(b) formulating a substantial portion of carbidopa into granules,minitablets or pellets; and

(c) formulating the product obtained in step (a) and product of step (b)and the rest of the drug substances, if any, into a monolayered,bilayered, threelayered or a multilayered tablet.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating substantial portion of levodopa and substantial portionof carbidopa either together or separately

(b) optionally granulating all or any portion of entacapone

(c) combining the product obtained in step a) with the product obtainedin step (b), or entacapone as such or a mixture thereof; and

(d) formulating the product obtained in step (c) an the rest of levodopaand/or carbidopa, if any, into tablets or minitablets or filling thesame directly into capsules, sachets or a dispenser. Preferably,levodopa and carbidopa are granulated together.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating levodopa and carbidopa either together or separately

(b) granulating entacapone

(c) combining the product obtained in step a) with the product obtainedin step (b); and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling it or said minitablets into capsules, sachets ora dispenser. Preferably, levodopa and carbidopa are granulated together.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating levodopa and carbidopa either together or separately

(b) granulating from 5 to 100% of entacapone

(c) combining the product obtained in step a) with the product obtainedin step (b); and the rest of entacapone as such; and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling the same directly into capsules, sachets or adispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(ii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating levodopa and carbidopa either together or separately

(b) granulating from 10 to 75% of entacapone

(c) combining the product obtained in step a) with the product obtainedin step (b); and the rest of entacapone as such; and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling the same directly into capsules, sachets or adispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.68:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating levodopa and carbidopa either together or separately

(b) granulating from 15 to 50% of entacapone

(c) combining the product obtained in step a) with the product obtainedin step (b); and the rest of entacapone as such; and

(d) formulating the product obtained in step (c) into tablets orminitablets or filling the same directly into capsules, sachets or adispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg.

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) granulating levodopa and carbidopa either together or separately

(b) combining the product obtained in step (a) with entacapone as such;and

(c) formulating the product obtained in step (b) into tablets orminitablets.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is

(a) formulating carbidopa and levodopa either together or independentlyinto granules, minitablets or pellets

(b) formulating entacapone into granules, minitablets or pellets; andfilling the products obtained in steps (a) and (b) into capsules,sachets or a dispenser.

Preferably, levodopa and carbidopa are formulated together.

Yet another suitable way of separating entacapone and carbidopa has beendescribed in WO 2010/108845 disclosing a dosage form comprising a) afirst mixture of 10 to 75% by weight of the total amount of levodopawith all entacapone present in the composition and b) a second mixtureof 25 to 90% by weight of total levodopa with all carbidopa present inthe composition and c) optionally, a third mixture comprising theremaining levodopa, if any. To accomplish the separation of carbidopaand entacapone, the two mixtures a) and b) are prepared such that theyare not both in powder form. The same principles, manufacturingprocesses and excipients as disclosed in WO 2010/108845 may be used toprepare the dosage form also according to the present invention.

Thus, in one embodiment of the invention a method for the preparation ofa oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg.

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

a) preparing a first mixture of 10 to 75% by weight of the total amountof levodopa with all entacapone present in the composition,

b) preparing a second mixture of 25 to 90% by weight of total levodopawith all carbidopa present in the composition; and

c) optionally preparing a third mixture comprising the remaininglevodopa; and

d) formulating the products obtained in steps (a) and (b) and optionally(c) independently into granules, tablets, minitablets or pellets andoptionally filling the said granules, minitablets or pellets intocapsules, sachets or a dispenser.

Preferably, when the products of step (a) and (b) are formulatedtogether, then (a) and (b) are not both in powder form.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

a) granulating from 10 to 75% by weight of the total amount of levodopawith all entacapone present in the composition,

b) granulating from 25 to 90% by weight of total levodopa with allcarbidopa present in the composition; and

c) optionally preparing a third mixture comprising the remaininglevodopa; and

d) formulating the products obtained in steps (a) and (b) and (c) if anyinto tablets or minitablets and optionally filling the said granules orminitablets into capsules, sachets or a dispenser.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

a) preparing a first mixture of 30 to 90% by weight of the total amountof levodopa with all entacapone present in the composition,

b) preparing a second mixture of 10 to 70% by weight of total levodopawith all carbidopa present in the composition; and

c) optionally preparing a third mixture comprising the remaininglevodopa; and

d) formulating the products obtained in steps (a) and (b) and optionally(c) independently into granules, tablets, minitablets or pellets andoptionally filling the said granules, minitablets or pellets intocapsules, sachets or a dispenser.

Preferably, when the products of step (a) and (b) are formulatedtogether, then product (a) and (b) are not both in powder form.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 160 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

a) preparing a first mixture of 50 to 80% by weight of the total amountof levodopa with all entacapone present in the composition,

b) preparing a second mixture of 20 to 50% by weight of total levodopawith all carbidopa present in the composition; and

c) optionally preparing a third mixture comprising the remaininglevodopa; and

d) formulating the products obtained in steps (a) and (b) and optionally(c) independently into granules, tablets, minitablets or pellets andoptionally filling the said granules, minitablets or pellets intocapsules, sachets or a dispenser.

Preferably, when the products of step (a) and (b) are formulatedtogether, then product (a) and (b) are not both in powder form.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

a) granulating 30 to 90% by weight of the total amount of levodopa withall entacapone present in the composition,

b) granulating of 10 to 70% by weight of total levodopa with allcarbidopa present in the composition; and

c) optionally preparing a third mixture comprising the remaininglevodopa; and

d) formulating the products obtained in steps (a) and (b) and (c) ifany, into tablets or minitablets and optionally filling the saidgranules or minitablets into capsules, sachets or a dispenser.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

a) granulating 50 to 80% by weight of the total amount of levodopa withall entacapone present in the composition,

b) granulating of 20 to 50% by weight of total levodopa with allcarbidopa present in the composition; and

c) optionally preparing a third mixture comprising the remaininglevodopa; and

d) formulating the products obtained in steps (a) and (b) and (c) ifany, into tablets or minitablets and optionally filling the saidgranules or minitablets into capsules, sachets or a dispenser.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) preparing a mixture of optionally pre-processed levodopa, optionallypre-processed carbidopa and optionally pre-processed entacapone,

(b) formulating the product obtained in step (a) into granules, tablets,minitablets, pellets and optionally filling said granules, minitabletsor pellets into a capsule, sachet or a dispenser.

In a particular embodiment of the invention a method for the preparationof a oral solid dosage form comprising

(I) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided comprising

(a) preparing a mixture of optionally pre-processed levodopa, optionallypre-processed carbidopa and optionally pre-processed entacapone,

(b) compressing the product obtained in step (a) into tablets. Thismethod provides a simple and robust manufacturing process, wherein alsonon-micronized drug substances (for instance, medium sized or coarseentacapone) may be used.

In one embodiment of the invention an oral solid dosage form is providedcomprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, allowing 80-100% of levodopa to bereleased within one hour in a dissolution test (USP apparatus I(baskets) 50 rpm, medium: 0.1 N hydrochloric acid, volume 750 ml) fromsaid dosage form.

In one embodiment of the invention an oral solid dosage form is providedcomprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, allowing from 90 to 100% of levodopa tobe released within one hour in a dissolution test (USP apparatus I(baskets) 50 rpm, medium: 0.1 N hydrochloric acid, volume 750 ml) fromsaid dosage form.

In one embodiment of the invention an oral solid dosage form is providedcomprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, allowing from 20 to 100% of carbidopa tobe released within one hour in a dissolution test (USP apparatus I(baskets) 50 rpm, medium: 0.1 N hydrochloric acid, volume 750 ml) fromsaid dosage form.

In one embodiment of the invention an oral solid dosage form is providedcomprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, allowing from 40 to 100% of carbidopa tobe released within one hour in a dissolution test (USP apparatus I(baskets) 50 rpm, medium: 0.1 N hydrochloric acid, volume 750 ml) fromsaid dosage form.

In one embodiment of the invention an oral solid dosage form is providedcomprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, allowing from 20 to 100% of entacaponeto be released within 60 minutes in a dissolution test (USP apparatus I(baskets) 125 rpm, medium: phosphate buffer pH 5.5, volume 900 ml) fromsaid dosage form.

In one embodiment of the invention an oral solid dosage form is providedcomprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, allowing from 40 to 100% of entacaponeto be released within 60 minutes in a dissolution test (USP apparatus I(baskets) 125 rpm, medium: phosphate buffer pH 5.5, volume 900 ml) fromsaid dosage form.

The dosage form according to the invention may include, for instance oneor more of fillers, binders, disintegrants, solubility enhancers,glidants, lubricants (if applicable, for example, if tabletting) as wellas other pharmaceutical excipients. The maximum amount of excipients istypically from 50 to 60% by weight of the dosage form.

The amounts of the excipients depend on the choice of technology inquestion and whether the same technology, for example, granulation isused to formulate all drug substances. For example, in case wetgranulation is used to formulate all drug substances then the amount ofthe binder is typically from about 0.1% by weight to about 50% by weightof the total weight of the dosage form.

The amount of disintegrant is typically from about 1% by weight to about30% by weight of the total weight of the dosage form. A typical amountof a solubility enhancer is from about 1% by-weight to about 40% byweight of the total weight of the dosage form. A typical amount of adiluent or filler is from about 1% by weight to about 60% by weight ofthe total weight of the dosage form. A typical amount of a glidant isfrom about 0.1% by weight to about 20% by weight of the total weight ofthe dosage form. A typical amount of a lubricant is from about 0.1% byweight to about 10% by weight of the total weight of the dosage form. Atypical amount of a release rate controlling excipient is from about0.1% by weight to about 60% by weight of the total weight of the dosageform. A typical amount of a co-processed excipient is from about 1% byweight to about 60% by weight of the total weight of the dosage form.

In one embodiment the dosage form according to the invention comprises adiluents or a filler which may be used e.g. as a processing aid. Thediluents or filler may be, for instance one or more of calcium carbonate(Barcroft, Cal-Carb, CalciPure, Destab, MagGran, Millicarb. Pharma-Carb,Precarb, Sturcal, Vivapres Ca), calcium phosphate, dibasic anhydrous(A-TAB, Di-Cafos A-N, Emcompress Anhydrous, Fujicalin), calciumphosphate, dibasic dihydrate (Cafos, Calipharm, Calstar, Di-Cafos,Emcompress), calcium phosphate tribasic (Tri-Cafos, TRI-CAL WG,TRI-TAB), calcium sulphate (Destab, Drierite, Snow White, Cal-Tab,Compactrol, USG Terra Alba), cellulose powdered (Arbocel, Elcema,Sanacel, Solka-Floc), silicified microcrystalline cellulose (ProSolv),cellulose acetate, compressible sugar (Di-Pac), confectioner's sugar,dextranes (Candex, Emdex), dextrin (Avedex, Caloreen, Crystal Gum,Primogran W), dextrose (Caridex, Dextrofin, Lycadex PF, Roferose, Tabfine D-IOO), fructose (Advantose, Fructamyl, Fructofin, Krystar),kaolinLion, Sim 90), lactitol (Finlac ACX, Finlac DC, Finlac MCX)lactose (Aero Flo 20, Aero Flo 65. Anhydrox, Capsulac, Fast-Flo,FlowLac, GranuLac, InhaLac, Lactochem, Lactohale, Lactopress, Microfine,Microtose, Pharmatose, Prisma Lac, Respitose, SacheLac, SorboLac,Super-Tab, Tablettose, Wyndale, Zeparox), magnesium carbonate, magnesiumoxide (MagGran MO), isomalt (Galen IQ, Isomaltidex, Palatinit),matodextrin (C*Dry MD, Glucidex, Glucodry, Lycatab DSH, Maldex,Maltagran, Maltrin, Maltrin QD, Paselli MD 10 PH, Star-Dri), maltitol(C*PharmMaltides, Maltisorb, D-maltitol, Maltit, Amalty, Malbit) maltose(Advantose 100), mannitol (Mannogem, Pearlitol), microcrystallinecellulose (Avicel PH, Celex, Celphere, Ceolus KG, Emcocel, Ethispheres,Fibrocel, Pharmacel, Tabulose, Vivapur), polydextrose (Litesse),simethicone (Dow Corning Q7-2243 LVA, Cow Corning Q7-2587. SentrySimethicone), sodium alginate (Kelcosol, Keltone, Protanal), sodiumchloride (Alberger), sorbitol (Liponec 70-NC, Liponic 76-NC, Meritol,Neosorb, Sorbifin, Sorbitol Instant, Sorbogem), starch (Aytex P. FluftexW, Instant Pure-Cote, Melojel, Meritena Paygel 55, Perfectamyl D6PH,Pure-Bind, Pure-Cote, Pure-Dent, Pure-Gel, Pure-Set. Purity 21, Purity826, Tablet White), pregelatinized starch (Instastarch, Lycatab C,Lycatab PGS, Merigel, National 78-1551, Pharma-Gel, Prejel, Sepistab ST200, Spress B820, Starch 1500 G, Tablitz, Unipure LD, Unipure WG220),sucrose, trehalose and xylitol (Klinit, Xylifm, Xylitab, Xylisorb,Xylitolo).

In one embodiment the dosage form of the invention comprises a binder.The binder may be, for instance one or more of following: acacia,alginic acid (Kelacid, Protacid, Satialgine H8), carbomer (Acritamer,Carbopol, Pemulen, Ultrez), carboxymethylcellulose sodium (Akucell,Aquasorb. Blanose, Finnfix, Nymcel, Tylose), ceratonia (Meyprofleur),cottonseed oil, dextrin (Avedex, Caloreen, Crystal Gum, Primogran W),dextrose (Caridex, Dextrofm, Lycedex PF, Roferose, Tabfme D-IOO),gelatin (Cryogel, Instagel, Solugel), guar gum (Galactosol, Meprogat,Meyprodor, Meyprofm, Meyproguar), hydrogenated vegetable oil type I(Akofine, Lubritab, Sterotex, Dynasan P60, Softisan 154, Hydrocote,Lipovol, HS-K, Sterotex HM), hydroxyethyl cellulose (Alcoramnosan,Cellosize, Idroramnosan, Liporamnosan, Natrosol, Tylose PHA),hydroxyethylmethyl cellulose (Culminal, Tylopur MH, Tylopur MHB, Tylose,MB, Tylose MH, Tyose MHB), hydroxypropyl cellulose (Klucel, Methocel,Nisso HPC), low substituted hydroxypropyl cellulose, hypromellose(Benecel MHPC, Methocel, Metolose, Pharmacoat, Spectracel 6, Spectracel15, Tylopur), methylcellulose (Benecel, Culminal MC), magnesiumaluminium silicate (Carrisorb, Gelsorb, Magnabite, Neusilin, Pharmsorb,Veegum), maltodextrin (C*Dry, MD. Glucidex, Glucodry, Lycatab DSH,Madex, Maltagran, Maltrin, Maltrin QD, Paselli MD 10 PH, Star-Dri)maltose (Advantose 100), methylcellulose (Benecel, Culminal MC,Methocel, Metolose), microcrystalline cellulose (Avicel PH, Celex,Celphere, Ceolus KG, Emcocel, Ethispheres, Fibrocel, Pharmacel,Tabulose, Vivapur), polydextrose (Litesse), polyethylene oxide (Polyox),polymethacrylates (Eastacryl 30D, Eudragit, Kollicoat MAE 30D, KollicoatMAE 30DP), povidone (Kollidon, Plasdone), sodium alginate (Kelcosol,Keltone, Protanal), starch (Aytex P, Fluftex W, Instant Pure-Cote,Melojel, Meritena Paygel 55, Perfectamyl D6PH, Pure-Bind, Pure-Cote,Pure-Dent, Pure-Gel, Pure-Set, Purity 21, Purity 826, Tablet White),pregelatinized starch (Instastarch, Lycatab C, Lycatab PGS, Merigel,National 78-1551, Pharma-Gel, Prejel, Sepistab ST 200, Spress 8820,Starch 1500 G, Tablitz, Unipure LD, Unipure WG 220), stearic acid(Crodacid, Emersol Hystrene, Industrene, Kortacid 1895, Pristerene),sucrose and zein.

In one embodiment of the invention the binder is a binder suitable foruse in hot melt granulation (hot melt binder). Such a binder may be, forexample one or more of the following: Polyethylene glycol (Breox PEG,Carbowax, Hodag PEG, Lutrol E), Stearic acid, Paraffin, Castor oil,hydrogenated (Castorwax, Castorwax MP 70. Castorwax MP 80, Opalwax,Sinulsol), Carnauba wax. Candelilla wax, Cottonseed oil, hydrogenated(Lubritab, Sterotex), glyceryl monostearate (Advawax 140, Atmul 67,Citomulgin M, Estol 603, Hodag GMS, Myvaplex 600P), acetylated glycerolmonostearate, sorbitan monostearate (Capmul S, Liposorb S, ProtachemSMS, Span 60), hexadecyl palmitate, octadecyl stearate, glyceryltrimyristate (Dynasan 114), glyceryl trilaurate (Dynasan 112), glyceryltripalmitate (Dynasan 116), glyceryl tristearate (Dynasan 118) andglyceryl behenate (Compritol 888 Ato).

In one embodiment the dosage form according to the invention comprises adisintegrant. The disintegrant maybe, for instance one or more offollowing: alginic acid (Kelacid, Protacid, Satialgine H8), calciumphosphate, tribasic (Tri-Cafos, TRI-CAL WG, TRI-TAB),carboxymethylcellulose calcium (ECG 505, Nymcel ZSC),carboxymethylcellulose sodium (Akucell, Aquasorb, Blanose, Finnfix,Nymcel Tylose CB), colloidal silicon dioxide (Aerosil, Cab-O-Sil,Cab-O-Sil M-5P, Wacker HDK), croscarmellose sodium (Ac-Di-Sol, Explocel,Nymcel ZSX, Pharmacel XL, Primellose, Solutab, Vivasol), crospovidone(Kollidon CL, Kollidon CL-M, Polyplasdone XL, Polyplasdone XL-IO),docusate sodium, guar gum (Galactosol, Meprogat, Meyprodor, Meyprofin,Meyproguar), low substituted hydroxypropyl cellulose, magnesium aluminunsilicate (Carrisorb, Gelsorb, Magnabite, Neusilin, Pharmsorb, Veegum),methylcellulose (Benecel, Culminal MC, Methocel, Metolose),microcrystalline cellulose (Avicel PH, Celex, Celphere, Ceolus KG.Emcocel, Ethispheres, Fibrocel, Pharmacel, Tabulose, Vivapur), povidone(Kollidon, Plasdone) sodium alginate (Kelcosol, Keltone, Protanal),sodium starch glycolate (Explotab, Primojel, Vivastar P), polacriflinpotassium (Amberlite IRP88), silicified microcrystalline cellulose(ProSolv), starch (Aytex P, Fluftex W, Instant Pure-Cote, Melojel,Meritena, Paygel 55, Perfectamyl D6PH, Pure-Bind, Pure-Cote, Pure-Dent,Pure-Gel, Pure-Set, Purity 21, Purity 826. Tablet White) orpregelatinized starch (Instanstarch, Lycatab C, Lycatab PGS, Merigel,National 78-1551, Pharma-Gel, Prejel, Sepistab ST 200, Spress B820,Starch 1500 G, Tablitz, Unipure LD and Unipure WG220).

In one embodiment the dosage form according to the invention comprises asolubility enhancer. The solubility enhancer may be, for instance one ormore of the following: cyclodextrins (Cavitron, Encapsin, Rhodocap,Kleptose), glyceryl monostearate (Abracol SLG, Admul, Myvaplex 600P),lecithin, poloxamer (Lutrol, Monolan, Pluronic), polyoxyethylene fattyacid esters (polysorbates) (Tween), polyoxyethylene castor oilderivatives (Cremophor series), docusate sodium (Cropol), sodium laurylsulphate (Elfan 240, Maprofix 563), sorbitan esters (sorbitan fatty acidesters) (Span), polyvinyl pyrrolidone, polyethylene glycol (PEG), laurylmacrogol glyceride (Gelucire) and d-alpha-tocophenyl PEG succinate(Vitamin E TPGS NF).

In one embodiment the dosage form according to the invention comprises arelease rate controlling excipient. The release controlling excipientmay be, for instance one or more of hydroxypropyl cellulose,hypromellose, hydroxy ethyl cellulose, ethyl cellulose, celluloseethers, poly(ethylene oxide), microcrystalline cellulose, carbomer,carbomers, carbomer copolymer, povidone (Kollidon, Plasdone) polyvinylacetate-povidone (Kollidon SR), fatty acids, fatty acid esters,magnesium stearate, calcium stearate, stearic acid, stearyl alcohol,glyceryl monostearate (Capmul GMS-50, Cutina GMS, Imwitor 191 and 900,Kessco GMS5 Lipo GMS 410, 450 and 800, Myvaplex 600P, Myvatex, ProtachemGMS-450, Rita GMS, Stepan GMS, Tegin, Tegin 503 and 515, Tegin 4100,Tegin M, Unimate GMS), glyceryl behenate (Compritol 888 ATO), glycerylpalmitostearate Precirol ATO 5) hydrogenated castor oil (Castorwax,Castorwax MP 70, Castorwax MP 80, Croduret, Cutina HR, Fancol, Simulsol1293), hydrogenated vegetable oil type I (Akofine, Lubritab. Sterotex,Dynasan P60, Softisan 154, Hydrocote, Lipovol HS-K. Sterotex HM),carnauba wax, shellac, rosin, zein, traganth gum, xanthan gum, guar gum,locust bean gum (Ceratoria). Other examples of suitable polymers include(but are not limited to) cellulose acetate, cellulose acetate phthalate,hypromellose phthalate, hypromellose acetate succinate, polyvinylacetate, polyvinyl acetate phthalate, alginic acid and its salts likesodium alginate, potassium alginate, calcium alginate, propylene glycolalginate. Also a release rate controlling agent may be acrylic acidpolymers and copolymers like methyl acrylate, ethyl acrylate, methylmethacrylate and/or ethyl methacrylate with copolymers of acrylic andmethacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS, EudragitFS30D, Eudrgit L, Eudragit S, Eudragit S100, Eudragit L100-55, RS30D,RL30D, NE30 D, Kollicoat MAE 30D, Kollicoat MAE 30DP, Acryl EZE, AcrylEZE-MP, Eastacryl 30D) and the like and any mixture or combinationthereof, cellulose acetate, cellulose diacetate, cellulose triacetate,cellulose acetate phthalate, polyvinyl acetate phthalates, hydroxypropylmethylcellulose phthalates, hydroxypropyl methylcellulose acetatesuccinates LF, hydroxypropyl methylcellulose acetate succinate HF, andothers.

In one embodiment the dosage form according to the invention comprises aglidant. The glidant may be, for instance one or more of the following:tribasic calcium phosphate (Tri-Cafos, TRI-CAL, TRI-TAB), calciumsilicate, cellulose, powdered (Arbocel, Elcema, Sanacel, Solka-Floc),colloidal silicon dioxide (Aerosil, Cab-O-Sil, Cab-O-Sil M-5P, WackerHDK), magnesium silicate, magnesium trisilicate, starch (Aytex P,Fluftex W, Instant Pure-Cote, Melojel, Meritena, Paygel 55, PerfectamylD6PH, Pure-Bind, Pure-Cote, Pure-Dent, Pure-Gel, Pure-Set, Purity 21,Purty 826, Tablet White) and talc (Altaic, Luzenac, Luzenac Pharma,Magsil Osmanthus, Magsil Star, Superiore).

In one embodiment the dosage form is a tablet or a core tablet and alubricant may be used to improve the tabletting. The lubricant may befor instance one or more of following: calcium stearate (HyQual),glycerine monostearate (Capmul GMS-50, Cutina GMS, Imwitor 191 and 900,Kessco GMS5 Lipo GMS 410, 450 and 600, Myvaplex 600P, Myvatex, ProtachemGMS-450, Rita GMS, Stepan GMS, Tegin, Tegin 503 and 515, Tegin 4100,Tegin M, Unimate GMS), glyceryl behenate (Compritol 888 ATO), glycerylpalmitostearate Precirol ATO 5), hydrogenated castor oil (Castorwax,Castorwax MP 70, Castorwax MP 80, Croduret, Cutina HR, Fancol, Simulsol1293), hydrogenated vegetable oil type I (Akofine, Lubritab, Sterotex,Dynasan P60, Softisan 154, Hydrocote, Lipovol HS-K, Sterotex HM),magnesium lauryl sulphate, magnesium stearate, medium-chaintriglycerides (Captex 300, Captex 355, Crodamol GTC/C, Labrafac CC,Miglyol 810, Miglyol 812, Myritol, Neobee M5, Nesatol, Waglinol 3/9280),poloxamer (Lutrol, Monolan, Pluronic, Supronlcm, Synperonic),polyethylene glycol (Carbowax, Carbowax Sentry, Lipo, Lipoxol, Lutrol E,Pluriol E), sodium benzoate (Antimol), sodium chloride (Alberger),sodium lauryl sulphate (Elfan 240, Texapon KI 2P), sodium stearylfumarate (Pruv), stearic acid (Crodacid E570, Emersol, Hystrene,Industrene, Kortacid 1895, Pristerene), talc (Altalc, Luzenac, LuzenacPharma, Magsil Osmanthus, Magsil Star, Superiore), sucrose stearate(Surfhope SE Pharma D-1803 F) and zinc stearate (HyQual).

In one embodiment the dosage form according to the invention comprisesas co-processed excipients any combinations of these components which bytheir functions for improv said properties. Some of them arecommercially available like cellulose and silicified microcrystalline(ProSolv) or microcrystalline cellulose-silicon dioxide-sodium starchglycolate and sodium stearyl fumarate (ProSolv EASYtab).

In one embodiment of the invention the tablet, minitablet, granuleand/or the pellet disclosed herein may be coated. In one embodiment ofthe invention the coating comprises one or more of the followingpolymers: a cellulose derivative, polyvinyl alcohol, polyethyleneglycols, acrylate polymers or a sugar derivative. Preferably, a waterbased coating is used. The coating may comprise plasticizers, dyes,colour lakes, or pigments, such as iron oxides, for instance yellow orred irons oxides and titanium dioxide.

Entacapone used in the dosage form of the invention is preferably asubstantially pure (E)-isomeric form the preparation of which has beendisclosed in U.S. Pat. No. 5,135,950. The (E)-isomer may take differentpolymorphic forms, e.g. polymorph A disclosed in U.S. Pat. No. 5,135,950or polymorph D disclosed in WO 2005/063696.

The water solubility of entacapone is rather slow. Due to poorsolubility, the dissolution rate of entacapone can be a limiting factorfor the absorption of entacapone in the gastrointestinal tract. WO2006/131591 discloses that in order to facilitate the absorption,entacapone having reduced particle size (i.e. at least 90% of entacaponeparticles have a diameter less than 55 microns e.g. less than 35microns) is preferably used when making granules comprising entacapone.The specific surface area (SSA) of such fine particles of entacapone istypically higher than 2.0 m²/g.

Thus, in one embodiment of the invention a method for the preparation ofa oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation ofsaid dosage form entacapone has been used having specific surface areaof from 2 m²/g to 20 m²/g.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form entacapone has been used having specific surfacearea of from 2.2 m²/g to 7 m²/g.

Entacapone particles of reduced particle size, however, have tended tocause manufacturing problems. Potential problems related to fineparticle size include poor flowability and agglomeration which mayresult in compromised content uniformity (i.e. the reproducible amountof entacapone between different units). The use of coarser particle sizewould therefore be beneficial. Such a coarser particle size could beused, for example, in direct compression which is advantageous, asdirect compression is an inexpensive and efficient manufacturingprocess. It has now been surprisingly found out by the applicants thatis not necessary (but it is still possible) to use such a small particlesize of entacapone when preparing the dosage forms according to theinvention. Quite to the contrary, when using particle sizes ofentacapone larger than the ones disclosed in WO 2006/131591 it ispossible to influence the pharmacokinetic profile of levodopa byreducing the time to Cmax i.e. Tmax. Reduced Tmax could be highlyvaluable to a patient who has troublesome early-morning parkinsoniansymptoms such as akinesia, rigidity and foot dystonia.

Thus, in one embodiment of the invention a method for the preparation ofa oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form entacapone has been used having specific surfacearea of from 0.2 m²/g to less than 2 m²/g. Entacapone particles having aSSA from 0.2 m²/g to 2 m²/g are considered to consist mainly of mediumsized particles.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form entacapone has been used having specific surfacearea of from 0.2 m²/g to 1.0 m²/g.

Still in another embodiment of the invention a method for thepreparation of a oral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form entacapone has been used having specific surfacearea of from 0-01 to less than 0.2 m²/g. Entacapone particles having aSSA from 0.01 m² to 0-2 m 2 are considered to consist mainly of coarsesized particles.

The particle size of levodopa for use in the dosage form of the presentinvention may be a particle size as typically used in formulationscomprising levodopa. The particle size of commercially availablelevodopa may generally be suitable.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form entacapone has been used having specific surfacearea of from 0.1 to 0.2 m²/g.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.68:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form levodopa has been used having specific surface areaof from 0.1 to 1.0 m²/g.

The particle size of carbidopa for use in the dosage form of the presentinvention may be a particle size as typically used in formulationscomprising carbidopa.

In one embodiment of the invention a method for the preparation of aoral solid dosage form comprising

(i) levodopa in an amount ranging from 50 mg to 200 mg,

(ii) carbidopa in an amount ranging from 65 mg to 150 mg or atherapeutically equivalent amount of another aromatic amino aciddecarboxylase inhibitor, and

(iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein theproportion of entacapone to carbidopa in said dosage form ranges from0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparationof said dosage form carbidopa has been used having specific surface areaof from 0.5 to 10 m²/g.

The SSA values are measured using three-point nitrogen gas adsorptionaccording to the BET (Brunauer-Emmett-Teller) technique well known inthe art (e.g. using Coulter SA3100, Coulter Corp. or TriStar 3000,Micromeritics, or other corresponding equipment).

The entacapone particles used in the dosage form(s) as well as in thepreparation thereof according to this disclosure can be produced by anymethod used in the art for obtaining particles with a desired specificsurface area and/or particles size distribution. Thus, they may beobtained directly from the production scale processes (e.g. by directcrystallization) or reducing the particle size of said entacaponeparticles for example mechanically (e.g. by milling, for instance by aball mill, a fluid energy attrition mill or a jet mill), by ultrasonicmeans and/or by fractionating. As a general textbook reference onproviding particles of desired size as well as to manufacturingtechnologies mentioned herein a reference is made to Remington'sPharmaceutical Sciences, 18^(th) ed, 1990, Mack Publishing Company,Easton, Pa. 18042. Suitable manufacturing technologies may be also foundin Pharmaceutics the Science of Dosage Form Design Ed. M. E. Auton,2000.

The particle size of aromatic amino acid decarboxylase inhibitor otherthan carbidopa and of COMT inhibitor other than entacapone may similarlybe the size typically used in formulations comprising these substances,and commercially available materials may be of a suitable particle size.

It is to be understood that whenever a method for the preparation agiven dosage form is mentioned herein in the context of this disclosureit is meant that this invention also comprises the dosage formsobtainable using said method. Thus, the present invention also relatesto dosage forms, particularly oral solid dosage forms, including singleunit dosage forms and multiple-unit dosage forms, comprising granules,tablets, minitablets, pellets, capsules, sachets or dispensersobtainable by the methods described above. It is further to beunderstood that any specific disclosure herein regarding amounts,ranges, excipients, particle size, manner of formulation, parameters,etc may be applied, as would be evident to the skilled person, to anyembodiment disclosed herein whether methods (e.g. methods for thetreatment of the body or methods of manufacture) or products, e.g.dosage forms.

The present disclosure also provides a kit for simultaneous orsequential administration of levodopa, carbidopa or a therapeuticallyequivalent amount of another aromatic amino acid decarboxylaseinhibitor, and entacapone, a moderately potent COMT inhibitor, or ahighly potent COMT inhibitor in the amounts described above. The kit maycomprise the levodopa, aromatic amino acid decarboxylase inhibitor (suchas carbidopa) and COMT inhibitor (such as entacapone) in anycombination. Thus, the kit may suitably be comprised of oral soliddosage forms in any combination of single and multi-unit dosage forms asdefined above. Thus, in one embodiment, a kit may be comprised of allsingle oral dosage forms as defined above. For example, such a kit mightcomprise a number of tablets, each of which comprise levodopa, carbidopaand entacapone, for individual administration at set time intervals.

In another embodiment, a kit may be comprised of all multi-unit dosageforms in the form of individual tablets containing the drug substances.By way of example, such a kit could comprise entacapone in one tabletand a separate tablet containing levodopa and carbidopa for sequentialadministration. In a further embodiment, a kit may comprise multi-unitdosage forms in the form of a plurality of oral solid units (i.e.multiple unit or multi-particulate dosage forms), e.g. a capsule, sachetor dispenser filled with minitablets, granules or pellets. In anotherembodiment, a kit may comprise one or more single oral dosage forms andone or more multi-unit dosage forms. Thus, a further example of a kitmay comprise (1) a single oral dosage form comprising a COMT inhibitor,levodopa and carbidopa and (2) further oral solid dosage forms (singleoral dosage forms or multi-unit dosage forms) for separateadministration which comprise levodopa and carbidopa and optionally thesame COMT inhibitor or a different COMT inhibitor, such as entacapone.

The present disclosure will be illustrated by the following non-limitingexamples.

EXAMPLES Example 1

The primary objective of the study was to evaluate the effects ofdifferent carbidopa dose levels on the pharmacokinetics (PKs) oflevodopa with and without concomitant administration of entacapone. Thiswas the first study to evaluate the effect of the combinations in arepeated dose setting in human subjects. Pharmacokinetics of levodopa inthe presence of AADC and COMT inhibition with substances like carbidopaand entacapone is complex and difficult to model based on single dose PKdata in humans, or animal models. However, it has been shown earlierthat levodopa PK in healthy subjects is similar to that seen in PDpatients and therefore the results of this study indicate how thelevodopa PK will be in PD patients and how the levodopa PK will predictsymptom control of PD.

A total of 25 human subjects were enrolled into the study. The studysubjects were randomly allocated to receive either 200 mg of entacaponeor corresponding placebo in each treatment period. Entacapone, or acorresponding placebo, was administered concomitantly with 100 mg oflevodopa and 25 mg of carbidopa at 3.5-hour intervals 4 times a day. Inaddition, the study subjects received in a randomised order in eachtreatment period one of the additional dose levels (0 mg, 25 mg, and 75mg) of carbidopa.

There were 3 treatment periods, one for each carbidopa dose level andfor the same subjects with cross-over design so that each subjectparticipated for the 3 periods. There were two groups with the samecarbidopa doses, one group with and one group without concomitantentacapone administration. By this study design, the effect ofentacapone on carbidopa dose escalation and subsequently to levodopa PKcould be assessed in repeated dose setting in humans.

Dose combinations were:

A: Entacapone 200 mg+levodopa 100 mg+carbidopa 25 mg

B: Entacapone 200 mg+levodopa 100 mg+carbidopa 50 mg

C: Entacapone 200 mg+levodopa 100 mg+carbidopa 100 mg

E: Levodopa 100 mg+carbidopa 25 mg

F: Levodopa 100 mg+carbidopa 50 mg

G: Levodopa 100 mg+carbidopa 100 mg

After the first and last dose of the day, the whole levodopa andcarbidopa plasma profiles were assessed and after the second and thirddose only the minimum concentrations (just before the next dose at 3.5and at 7.0 hours) were assessed. The results concerning levodopa aregiven in FIG. 1 and the results concerning carbidopa are given in FIG. 2.

The results demonstrate that in repeated dosing regimen, and with thepresence of entacapone, increasing the carbidopa dose will significantlyimprove levodopa pharmacokinetics in human subjects. Without entacapone,the carbidopa dose increase did not have such an effect. This means thatchanging the ratios of the three concomitantly (i.e. simultaneously) orsequentially administered drugs, levodopa pharmacokinetics andsubsequently treatment of signs and symptoms of Parkinson's disease canbe significantly improved

Example 2

The primary objective of the study was to evaluate the effects ofdifferent carbidopa dose levels on the pharmacokinetics (PKs) oflevodopa with concomitant administration of different entacapone doselevels and with the moderately potent COMT inhibitor tolcapone.

The study subjects were randomly allocated to receive either increasingdoses of entacapone or standard dose of tolcapone combined withincreasing doses of carbidopa in each treatment period, a total of 12different dose combinations. Entacapone was administered concomitantlywith 100 mg of levodopa and 25 mg of carbidopa at 3.5-hour intervals 4times a day and tolcapone 3 times a day. In addition, the study subjectsreceived increasing dose levels of carbidopa.

There were three groups, one for each carbidopa dose level, and 4treatment periods in each group, one for each entacapone dose level orfor tolcapone and for the same subjects with cross-over design so thatone subject participated for the 4 periods. By this study design theeffect of entacapone and tolcapone on carbidopa dose escalation andsubsequently to levodopa PK could be assessed in repeated dose settingin humans.

After each levodopa dose of the day, the levodopa plasma profile wasassessed. The levodopa plasma concentrations after entacapone doseescalation and tolcapone standard dose and with increased carbidopa doseare given in FIG. 3 .

The results demonstrate that in repeated dosing regimen, and with theincreased COMT-inhibition either by increasing the COMT-inhibitor doseor by using a more potent COMT-inhibitor, increasing the carbidopa dosewill significantly improve levodopa pharmacokinetics in human subjects.This means that changing the ratios of the three concomitantly (i.e.simultaneously) or sequentially administered drugs, levodopapharmacokinetics and subsequently treatment of signs and symptoms ofParkinson's disease can be significantly improved.

Example 3

The examples of suitable entacapone/levodopa/carbidopa tabletformulations are described in Tables 1 to 2 (formulations 1 to 4). Thetablets are prepared by adding carbidopa separately as granules into theformulation. Accordingly, entacapone and levodopa are granulatedtogether with maize starch, mannitol, croscarmellose sodium and povidonein a high shear mixer. Carbidopa is wet granulated separately with maizestarch, mannitol, croscarmellose sodium, and povidone in a high shearmixer. The dry entacapone/levodopa granules, the dry carbidopa granules,croscarmellose sodium, mannitol (and castor oil, hydrogenated, informulations 3 to 4), and magnesium stearate are mixed together and themass obtained are compressed to tablets and coated with HPMC-coatingcontaining a color pigment.

TABLE 1 Proposed dosage forms of entacapone/levodopa/carbidopa100/100/80 (Formulation 1) and 200/100/80 (Formulation 2) tablet.Formulation 1 Formulation 2 Core tablet: mg/tablet mg/tablet Entacapone100.0 200.0 Levodopa 100.0 100.0 Carbidopa monohydrate 86.5 86.5(corresponds to anhydrate 80.0 mg) Maize starch 77.0 107.0 Mannitol141.3 159.7 Croscarmellose sodium 24.3 31.4 Povidone 32.4 47.9 Magnesiumstearate 8.5 10.5 Theoretical weight of the 570.0 743.0 core tabletHPMC-coating containing 17.0 21.0 color pigments Theoretical weight ofthe 587.0 764.0 coated tablet

TABLE 2 Proposed dosage forms of entacapone/levodopa/carbidopa100/100/80 (Formulation 3) and 200/100/80 (Formulation 4) tablet.Formulation 3 Formulation 4 Core tablet: mg/tablet mg/tablet Entacapone100.0 200.0 Levodopa 100.0 100.0 Carbidopa monohydrate 86.5 86.5(respond carbidopa 80.0 mg) Maize starch 77.0 107.0 Mannitol 152.7 173.7Croscarmellose sodium 12.9 17.4 Castor oil, hydrogenated 3.0 4.0Povidone 32.4 47.9 Magnesium stearate 8.5 10.5 Theoretical weight of the573.0 747.0 core tablet HPMC-coating containing 17.0 21.0 color pigmentsTheoretical weight of the 590.0 768.0 coated tablet

We claim:
 1. An oral dosage form comprising: (i) levodopa in an amountranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from65 mg to 125 mg, and (iii) entacapone in an amount ranging from 100 mgto 200 mg, wherein the proportion of entacapone to carbidopa in saiddosage form ranges from 0.8:1.0 to 3.08:1.0 by weight.
 2. The dosageform according to claim 1, wherein the proportion of entacapone tocarbidopa in said dosage form ranges from 1.6:1.0 to 1.9:1.0 by weight.3. The dosage form according to claim 1, wherein entacapone is presentin an amount of 200 mg, 150 mg, or 100 mg.
 4. The dosage form accordingto claim 1, wherein carbidopa is present in an amount of 65 mg, 80 mg,85 mg, 105 mg, or 125 mg.
 5. The dosage form according to claim 1,wherein the proportion of entacapone to carbidopa in said dosage form is0.8:1.0, 1.3:1.0, 1.6:1.0, 1.9:1.0, 2.4:1.0, 2.5:1.0, 2.4:1.0, or2.5:1.0 by weight.
 6. The dosage form according to claim 1, wherein theproportion of entacapone and carbidopa in said dosage form is 100 mg:125mg, 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200 mg:125mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, or 200 mg:65 mg.
 7. Thedosage form according to claim 1, wherein levodopa is present in anamount of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 200 mg.
 8. The dosageform according to claim 1, wherein the proportion of levodopa tocarbidopa in said dosage form ranges from 1.4:1.0 to 2.3:1.0 by weight.9. The dosage form according to claim 1, wherein the proportions oflevodopa, carbidopa and entacapone in said dosage form are 50 mg:65mg:200 mg, 50 mg:80 mg:200 mg, 50 mg:85 mg:200 mg, 50 mg:105 mg:200 mg,75 mg:65 mg:200 mg, 75 mg:80 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:80 mg:200 mg, 100 mg:85 mg:200mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:80 mg:200 mg, 125mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:80mg:200 mg, 150 mg:85 mg:200 mg, 150 mg:105 mg:200 mg, 200 mg:65 mg:200mg, 200 mg:80 mg:200 mg, 200 mg:85 mg:200 mg, or 200 mg:105 mg:200 mg.10. A method for the treatment of Parkinson's disease comprisingsimultaneously or sequentially orally administering to a patient in needof treatment of Parkinson's disease (i) levodopa in an amount rangingfrom 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to125 mg, and (iii) entacapone in an amount ranging from 100 mg to 200 mg,wherein the proportion of entacapone to carbidopa ranges from 0.8:1.0 to3.08:1.0 by weight, and wherein the total number of doses administeredper day of each of levodopa, carbidopa, and entacapone ranges from 3 to10.
 11. The method according to claim 10, wherein the treatmentcomprises administering orally an oral solid dosage form.
 12. The methodaccording to claim 10, wherein the proportion of entacapone to carbidoparanges from 1.90:1.0 to 3.08:1.0 by weight.
 13. The method according toclaim 10, wherein entacapone is present in an amount of 100 mg, 150 mg,or 200 mg.
 14. The method according to claim 10, wherein carbidopa ispresent in an amount of 65 mg, 80 mg, 85 mg, 105 mg, or 125 mg.
 15. Themethod according to claim 10, wherein the proportion of entacapone tocarbidopa is 0.80:1.0, 0.95:1.0, 1.18:1.0, 1.33:1.0, 1.54:1.0, 1.6:1.0,1.9:1.0, 2.35:1.0, 2.5:1.0, or 3.08:1.0 by weight.
 16. The methodaccording to claim 10, wherein the proportion of entacapone andcarbidopa is 100 mg:125 mg, 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg,100 mg:65 mg, 200 mg:125 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg,or 200 mg:65 mg.
 17. The method according to claim 10, wherein levodopais present in an amount of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 200mg.
 18. The method according to claim 10, wherein the proportion oflevodopa to carbidopa ranges from 0.71:1.0 to 2.31:1.0 by weight. 19.The method according to claim 10, wherein the proportions of levodopa,carbidopa and entacapone are 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200mg, 150 mg:65 mg:200 mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg.20. The method of claim 10, wherein the patient to be treated is anadult patient with Parkinson's disease experiencing symptoms ofend-of-dose wearing off.
 21. The method of claim 14, wherein the totalnumber of doses administered per day ranges from 3 to 7.